Dual Effect of Phosphate Transport on Mitochondrial Ca2+ Dynamics

Wei, An-Chi; Liu, Ting; O’Rourke, Brian

doi:10.1074/jbc.m114.628446

Cited by 19 publications

(17 citation statements)

References 44 publications

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“…The P i effect on mitochondrial buffering has an EC 50 of 0.096 mM (Wei et al . ). As we included 1 mM P i in our mitochondrial cocktail, Ca 2+ buffering within the matrix would have been maintained effectively in our experiments.…”

Section: Discussionmentioning

confidence: 97%

The whole‐cell Ca²⁺ release‐activated Ca²⁺ current, I_CRAC, is regulated by the mitochondrial Ca²⁺ uniporter channel and is independent of extracellular and cytosolic Na⁺

Samanta

Bakowski

Amin

et al. 2019

The Journal of Physiology

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Key pointsr Ca 2+ entry through Ca 2+ release-activated Ca 2+ channels activates numerous cellular responses. Under physiological conditions of weak intracellular Ca 2+ buffering, mitochondrial Ca 2+ uptake regulates CRAC channel activity.r Knockdown of the mitochondrial Ca 2+ uniporter channel prevented the development of I CRAC in weak buffer but not when strong buffer was used instead.r Removal of either extracellular or intra-pipette Na + had no effect on the selectivity, kinetics, amplitude, rectification or reversal potential of whole-cell CRAC current.r Knockdown of the mitochondrial Na + -Ca 2+ exchanger did not prevent the development of I CRAC in strong or weak Ca 2+ buffer.r Whole cell CRAC current is Ca 2+ -selective. r Mitochondrial Ca 2+ channels, and not Na + -dependent transport, regulate CRAC channels under physiological conditions. Abstract Ca 2+ entry through store-operated Ca 2+ release-activated Ca 2+ (CRAC) channels plays a central role in activation of a range of cellular responses over broad spatial and temporal bandwidths. Mitochondria, through their ability to take up cytosolic Ca 2+ , are important regulators of CRAC channel activity under physiological conditions of weak intracellular Ca 2+ buffering. The mitochondrial Ca 2+ transporter(s) that regulates CRAC channels is unclear and could involve the 40 kDa mitochondrial Ca 2+ uniporter (MCU) channel or the Na + -Ca 2+ -Li + exchanger (NCLX). Here, we have investigated the involvement of these mitochondrial Ca 2+ transporters in supporting the CRAC current (I CRAC ) under a range of conditions in RBL mast cells. Knockdown of the MCU channel impaired the activation of I CRAC under physiological conditions of weak intracellular Ca 2+ buffering. In strong Ca 2+ buffer, knockdown of the MCU

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Section: Discussionmentioning

confidence: 97%

The whole‐cell Ca²⁺ release‐activated Ca²⁺ current, I_CRAC, is regulated by the mitochondrial Ca²⁺ uniporter channel and is independent of extracellular and cytosolic Na⁺

Samanta

Bakowski

Amin

et al. 2019

The Journal of Physiology

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“…Mitochondrial were isolated using homogenization method on ice as previously described 99 . In brief, the heart was minced and homogenized in ice-cold isolation buffer (75 mM sucrose, 225 mM mannitol, 1 mM EGTA, and 0.2% fatty acid free BSA, pH 7.4) using a Potter-Elvehjem glass homogenizer.…”

Section: Mitochondrial Isolationmentioning

confidence: 99%

Mitochondrial CaMKII causes metabolic reprogramming, energetic insufficiency, and dilated cardiomyopathy

Luczak

Granger

et al. 2020

Preprint

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Despite the clear association between myocardial injury, heart failure and depressed myocardial energetics, little is known about upstream signals responsible for remodeling myocardial metabolism after pathological stress. We found increased mitochondrial calmodulin kinase II (CaMKII) activation and left ventricular dilation in mice one week after myocardial infarction (MI) surgery. In contrast, mice with genetic mitochondrial CaMKII inhibition were protected from left ventricular dilation and dysfunction after MI. Mice with myocardial and mitochondrial CaMKII over-expression (mtCaMKII) had severe dilated cardiomyopathy and decreased ATP that caused elevated cytoplasmic resting (diastolic) Ca 2+ concentration and reduced mechanical performance. We mapped a metabolic pathway that allowed us to rescue disease phenotypes in mtCaMKII mice, providing new insights into physiological and pathological metabolic consequences of CaMKII signaling in mitochondria. Our findings suggest myocardial dilation, a disease phenotype lacking specific therapies, can be prevented by targeted replacement of mitochondrial creatine kinase, or mitochondrial-targeted CaMKII inhibition. 7 10

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“…Additionally, the same study showed that the presence of 1 or 3 mM phosphate precludes [Ca 2+ ] m to reach higher concentrations because of the above-mentioned Ca 2+ buffering capacity of the phosphate. A third study also showed that the presence of Pi reduced by almost 50% the [Ca 2+ ] m reached (from an original value of 50 lM in the absence of Pi) [109]. The role of the Pi as a mitochondrial Ca 2+ buffer as well as the still under debate calcium-free/bound ratio [107,110,111] creates an extremely complex scenario where accurate and precise measurement of [Ca 2+ ] m is critical.…”

Section: Possible Explanations For the Discrepancies In [Ca 2+ ] M Rementioning

confidence: 99%

Mitochondrial Ca²⁺ concentrations in live cells: quantification methods and discrepancies

2019

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Intracellular Ca2+ signaling controls numerous cellular functions. Mitochondria respond to cytosolic Ca2+ changes by adapting mitochondrial functions and, in some cell types, shaping the spatiotemporal properties of the cytosolic Ca2+ signal. Numerous methods have been developed to specifically and quantitatively measure the mitochondrial‐free Ca2+ concentrations ([Ca2+]m), but there are still significant discrepancies in the calculated absolute values of [Ca2+]m in stimulated live cells. These discrepancies may be due to the distinct properties of the methods used to measure [Ca2+]m, the calcium‐free/bound ratio, and the cell‐type and stimulus‐dependent Ca2+ dynamics. Critical processes happening in the mitochondria, such as ATP generation, ROS homeostasis, and mitochondrial permeability transition opening, depend directly on the [Ca2+]m values. Thus, precise determination of absolute [Ca2+]m values is imperative for understanding Ca2+ signaling. This review summarizes the reported calibrated [Ca2+]m values in many cell types and discusses the discrepancies among these values. Areas for future research are also proposed.

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Dual Effect of Phosphate Transport on Mitochondrial Ca2+ Dynamics

Cited by 19 publications

References 44 publications

The whole‐cell Ca²⁺ release‐activated Ca²⁺ current, I_CRAC, is regulated by the mitochondrial Ca²⁺ uniporter channel and is independent of extracellular and cytosolic Na⁺

The whole‐cell Ca²⁺ release‐activated Ca²⁺ current, I_CRAC, is regulated by the mitochondrial Ca²⁺ uniporter channel and is independent of extracellular and cytosolic Na⁺

Mitochondrial CaMKII causes metabolic reprogramming, energetic insufficiency, and dilated cardiomyopathy

Mitochondrial Ca²⁺ concentrations in live cells: quantification methods and discrepancies

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Dual Effect of Phosphate Transport on Mitochondrial Ca2+ Dynamics

Cited by 19 publications

References 44 publications

The whole‐cell Ca2+ release‐activated Ca2+ current, ICRAC, is regulated by the mitochondrial Ca2+ uniporter channel and is independent of extracellular and cytosolic Na+

The whole‐cell Ca2+ release‐activated Ca2+ current, ICRAC, is regulated by the mitochondrial Ca2+ uniporter channel and is independent of extracellular and cytosolic Na+

Mitochondrial CaMKII causes metabolic reprogramming, energetic insufficiency, and dilated cardiomyopathy

Mitochondrial Ca2+ concentrations in live cells: quantification methods and discrepancies

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About

The whole‐cell Ca²⁺ release‐activated Ca²⁺ current, I_CRAC, is regulated by the mitochondrial Ca²⁺ uniporter channel and is independent of extracellular and cytosolic Na⁺

The whole‐cell Ca²⁺ release‐activated Ca²⁺ current, I_CRAC, is regulated by the mitochondrial Ca²⁺ uniporter channel and is independent of extracellular and cytosolic Na⁺

Mitochondrial Ca²⁺ concentrations in live cells: quantification methods and discrepancies